Bottom Line:
Improper adaptation is particularly important because it allows cell sub-populations to survive even in the continuous presence of death conditions, which results, among others, in the eventual failure of many targeted anticancer therapies.Here, I show that these typical responses arise naturally from the interplay of intracellular variability with a threshold-based control mechanism that detects cellular changes in addition to just the cellular state itself.These results indicate that oncogenes like Bcl-xL, besides regulating absolute death values, can have a novel role as active controllers of cell-cell variability and the extent of adaptation.

Background: Cellular responses to death-promoting stimuli typically proceed through a differentiated multistage process, involving a lag phase, extensive death, and potential adaptation. Deregulation of this chain of events is at the root of many diseases. Improper adaptation is particularly important because it allows cell sub-populations to survive even in the continuous presence of death conditions, which results, among others, in the eventual failure of many targeted anticancer therapies.

Results: Here, I show that these typical responses arise naturally from the interplay of intracellular variability with a threshold-based control mechanism that detects cellular changes in addition to just the cellular state itself. Implementation of this mechanism in a quantitative model for T-cell apoptosis, a prototypical example of programmed cell death, captures with exceptional accuracy experimental observations for different expression levels of the oncogene Bcl-xL and directly links adaptation with noise in an ATP threshold below which cells die.

Conclusions: These results indicate that oncogenes like Bcl-xL, besides regulating absolute death values, can have a novel role as active controllers of cell-cell variability and the extent of adaptation.

Figure 5: Time evolution of the threshold distribution and adaptation. The ATP threshold distribution for the cell type "Bcl-xL 1E1" is shown at different time points after IL-3 growth removal together with the dynamics of the intracellular ATP level (red thick line). The distribution is normalized to the survival fraction S (a(t)). The values of the parameters of the model are the same as in Figure 2. In this case, adaptation observed in the late stages of the response is the result of the combined effects of high threshold variability with intracellular ATP adapting to a new steady state.

Mentions:
The threshold distribution of live cells evolves in time because cells die when their threshold is higher than the ATP level (Figure 5 and Additional File 1). For monotonously decreasing ATP levels, this time-dependent behavior can be expressed explicitly in mathematical terms as T(x, t) = (dS (x)/dx) Θ (a(t)-x), where Θ(a(t) - x) is the Heaviside step function, which is 1 when a(t) - x > 0 and 0, otherwise. The resulting distribution is normalized to the fraction of surviving cells, .

Figure 5: Time evolution of the threshold distribution and adaptation. The ATP threshold distribution for the cell type "Bcl-xL 1E1" is shown at different time points after IL-3 growth removal together with the dynamics of the intracellular ATP level (red thick line). The distribution is normalized to the survival fraction S (a(t)). The values of the parameters of the model are the same as in Figure 2. In this case, adaptation observed in the late stages of the response is the result of the combined effects of high threshold variability with intracellular ATP adapting to a new steady state.

Mentions:
The threshold distribution of live cells evolves in time because cells die when their threshold is higher than the ATP level (Figure 5 and Additional File 1). For monotonously decreasing ATP levels, this time-dependent behavior can be expressed explicitly in mathematical terms as T(x, t) = (dS (x)/dx) Θ (a(t)-x), where Θ(a(t) - x) is the Heaviside step function, which is 1 when a(t) - x > 0 and 0, otherwise. The resulting distribution is normalized to the fraction of surviving cells, .

Bottom Line:
Improper adaptation is particularly important because it allows cell sub-populations to survive even in the continuous presence of death conditions, which results, among others, in the eventual failure of many targeted anticancer therapies.Here, I show that these typical responses arise naturally from the interplay of intracellular variability with a threshold-based control mechanism that detects cellular changes in addition to just the cellular state itself.These results indicate that oncogenes like Bcl-xL, besides regulating absolute death values, can have a novel role as active controllers of cell-cell variability and the extent of adaptation.

Background: Cellular responses to death-promoting stimuli typically proceed through a differentiated multistage process, involving a lag phase, extensive death, and potential adaptation. Deregulation of this chain of events is at the root of many diseases. Improper adaptation is particularly important because it allows cell sub-populations to survive even in the continuous presence of death conditions, which results, among others, in the eventual failure of many targeted anticancer therapies.

Results: Here, I show that these typical responses arise naturally from the interplay of intracellular variability with a threshold-based control mechanism that detects cellular changes in addition to just the cellular state itself. Implementation of this mechanism in a quantitative model for T-cell apoptosis, a prototypical example of programmed cell death, captures with exceptional accuracy experimental observations for different expression levels of the oncogene Bcl-xL and directly links adaptation with noise in an ATP threshold below which cells die.

Conclusions: These results indicate that oncogenes like Bcl-xL, besides regulating absolute death values, can have a novel role as active controllers of cell-cell variability and the extent of adaptation.